Dispenser with diffuser

ABSTRACT

A system is disclosed for delivering a beneficial agent at a substantially constant rate over time. The system comprises (1) a wall formed of a microporous polymer, or (2) a wall formed in part of a microporous polymer with the remaining part of the wall formed of a semipermeable polymer. The wall in (1) surrounds a compartment comprising a flexible partition that separates the compartment into a first space containing the beneficial agent and a second space containing a swellable polymer. The wall in (2) surrounds a compartment comprising a flexible partition that separates the compartment into a first space in contact with the microporous wall and containing the beneficial agent, and a second space in contact with the semipermeable polymer containing an osmotically effective solute, or a swellable polymer. In operation, agent is delivered from the system by (a) fluid diffusing through the microporous wall into the second space causing the polymer to swell, or by (b) fluid being imbibed through the semipermeable wall into the second space causing the solute to dissolve and form a solution, or causing the polymer to swell, wherein in (a) or (b), the second space expands against the partition urging it to move into the first space and maintain the agent in a saturated state at the microporous wall, with the agent diffusing from the first space through fluid filled micropaths in the wall from the system at a substantially zero order rate over a prolonged period of time.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of U.S. patent application Ser. No.144,210, filed on Apr. 28, 1980, with both applications assigned to thesame assignee.

FIELD OF THE INVENTION

The invention pertains to a system comprising a microporous diffusor fordelivering a beneficial agent to a fluid environment of use at a zeroorder rate for an increased length of time at that rate.

BACKGROUND OF THE INVENTION

Today, more research than ever before is devoted for providing systemsthat can deliver a beneficial agent at a controlled rate of release toan environment of use over a specified period of time. For example, inU.S. Pat. Nos. 3,845,770 and 3,916,899 issued to inventors FelixTheeuwes and Takeru Higuchi, osmotic systems manufactured in the form ofosmotic systems are disclosed for delivering a beneficial agent at acontrolled rate to an environment of use. The systems disclosed in thesepatents comprise a semipermeable wall that surround a compartmentcontaining the agent. The wall is permeable to an external fluid,substantially impermeable to agent, and there is a passageway throughthe wall for delivering the agent from the system. These systems releasethe agent by fluid being imbibed through the wall into the compartment,at a rate determined by the permeability of the wall and the osmoticpressure gredient across the wall, to produce a solution of the agent,that is dispensed through a passageway from the system. In U.S. Pat. No.4,111,202, issued to Patentee Felix Theeuwes, an osmotic system isdisclosed comprising a semipermeable wall that surrounds a first andsecond compartment. The first compartment contains a drug and the secondcompartment contains an osmotically effective solute. A passagewaythrough the semipermeable wall connects the exterior of the system withthe first compartment. The system releases agent by fluid being inbidedinto the first compartment to prepare drug formulation and by fluidbeing imbided into the second compartment causing it to increase involume, expand into and decrease the volume of the first compartment,whereby the agent is delivered through the passageway from the system.

While the above systems are outstanding and represent a pioneeradvancement in the delivery art, and while they are endowed with idealdelivery kinetics useful for delivering numerous and diverse beneficialagents at a controlled and continuous rate to many environments of use,there is an occasional instance where the delivery kinetics of thesystems can be unexpectedly modified to lead to more desirable results.For example, one of the important factors that should be considered indesigning a controlled release system is to maintain a constantthermodynamic activity of beneficial agent within the system. Thepresence of this constant activity source establishes a steady state, sothat agent is released from the system at a constant rate over time.This phenomenon is commonly referred to as zero order release.

If, however, a constant thermodynamic activity of agent is notmaintained within the system and the released agent is not replenished,because the system lacks excess agent or a means for keeping the agentin a saturated state, the release rate falls exponentially and theamount of agent released can also become unpredictable over time. Theselatter conditions occur because less and less agent is available at thereleasing diffusion boundary layer of the system and the quantityavailable for diffusion can be dependent on the degree of agitation.These release pattern is called first order release.

It will be appreciated by those versed in the delivery art that in manyapplications, for example in the pharmaceutical, veterinary andagriculature industries, the zero order release is the more preferredrelease. This is so because precise delivery of an agent in known andconstant amounts per unit time can lead to improve usage, and also inmany instances minimize deleterious effects to the environment,organisms and plants. Also, through controlled release, the efficacy ofagents may be enhanced, and the use of agents exhibiting high potenciesor low stabilities may prove more managable and economical over time. Itwill be further appreciated in view of this presentation, that if asystem is provided that can exhibit a substantially zero order releaseover time, the system would have a positive commercial use and alsorepresent a major contribution to the delivery art.

OBJECT OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide asystem that has useful thermodynamic physico-chemical properties fordelivering a beneficial agent over time.

Another object of the invention is to provide a system that has adelayed, diminishing boundary layer for increasing the amount of agentdelivered at a zero order release rate over time.

Yet another object of this invention is to provide a system having aconstant activity source by providing a system comprising a wall and aninternal expandable force that operates to maintain agent within thesystem in a saturated state at the releasing agent wall interface in thesystem.

Still another object of the invention is to make available a system fordelivering an agent, whose release is controlled by Fickian diffusionthrough fluid-filled paths in a microporous wall, with the agentactivity at the internal boundary layer kept at substantially saturatedlevel for an increased agent release period.

Yet still another object of the invention is to make available a systemthat delivers a beneficial agent at a prolonged substantially constantrate by delaying the appearance of a diminishing agent boundaryinterface and its accompanying drop in the delivery rate by providing asystem that substantially maintains the agent at a saturated level atthe boundary interface for an increased length of time.

Still yet another object of this invention is to make available adelivery system that exhibits a more constant, predictable release rateprofile of useful agent.

Still another object of the invention is to provide a novel and usefuldelivery system manufactured in the form of a delivery device with adiffusor for delivering agent from the system over time.

Other objects, features, aspects and advantages of the invention will bemore apparent to those versed in the art from the following detailedspecification, taken in conjunction with the figures and theaccompanying claims.

SUMMARY OF THE INVENTION

This invention concerns a system for delivering a beneficial agent to anenvironment of use. The system consists essentially of a microporouswall, or a part microporous part semipermeable wall surrounding acompartment having a space containing the agent separated by a partitionfrom a space containing an expandable entity. The entity consists of anosmotically effective solute, or a swellable polymer. In operation,agent is released from the system by the combined integratedphysical-chemical actions of the system, the agent and the entity. Theactions embrace agent diffusing through paths in the microporous wall,the entity expanding or continuously filling its space, and expandinginto the agent space, thereby delaying the appearance of a diminishing,diffusional boundary layer. The combined actions cause the agent to bedelivered from the system at a controlled and substantially zero-orderrate of release over an increased, prolonged period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1 is a view of a delivery system designed and shaped foradministering orally a beneficial drug to a warmblooded animal;

FIG. 2a is an opened view of the system of FIG. 1, which FIG. 2aillustrates the internal structure of the system consisting essentiallyof two spaces separated by a partition, with one space containing ameans for increasing the fraction of agent delivered at zero order overtime by maintaining the saturated state of agent in the integral unitmanufactured as a device;

FIG. 2b is the system of FIG. 1 with a section removed for depicting theinternal structure of the system manufactured with a partition, adifferent external wall structure, an agent housing space and acontacting expanding means for increasing the fraction of agent presentin a saturated state in the system;

FIG. 3 illustrates, in opened section, a system provided by theinvention, said system shaped and dimensioned for dispensing a drug in abody passageway such as the vagina, or the ano-rectal passageway;

FIG. 4 is a graph that illustrates the increase in time that can beachieved from S₁ to S₂ if an agent is maintained in a saturated state,thereby concomitantly delaying a premature appearance of the recedingdiffusional boundary layer; and,

FIG. 5 is an opened view showing a longitudinal section of a screwextruder used for blending agent formulations housed in the systems ofthe invention.

In the drawings and specification, like parts in related figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further discussed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which drawings are examples ofvarious delivery systems of the invention, and which examples are not tobe considered limiting, one example of a system is indicated in FIG. 1by the numeral 10. In FIG. 1, system 10 comprises a body 11, that isshaped, sized, structured and adapted for easy placement and prolongedretention in an environment of use for the controlled, continuousdelivery of a beneficial agent thereto.

In FIG. 2a system 10 of FIG. 1 is seen in opened-section with a part ofits outer layer removed for elucidating the total structure of system10. In FIG. 2a, system 10 comprises a body 11 having an exterior wall 12that surrounds an internal space having a partition 14 that separatesthe space into a first space 15 and a second space 16. Space 16 containsa swellable polymer 18, that on swelling in the presence of water exertspressure on partition 14 causing it to move and occupy volume in space15. The actions of partition 14 and polymer 18 combine to decrease thevolume of space 15, thereby functioning to maintain beneficial agent 17in a saturated state in space 15, especially during the time system 10is in operation in a prechosen environment of use.

In FIG. 2a, wall 12 of device 10 is formed of a microporous polymericmaterial containing a plurality of microscopic-sized interconnectedpores or voids. The pores, illustrated as circles 13 for discussionherein, can be continuous with openings on both sides of wall 12, thepores can be interconnected through tortuous paths of regular andirregular shapes, including curved, curved-linear, randomly orientedcontinuous paths, hindered connected paths and pores, and other pathsand pores discernible by microscopic examination. Generally, materialspossessing from 5 to 95% pores, more preferably a void space of 30% to90%, and having a pore size of 100 angstroms to 200 microns can be usedfor making wall 12. The pores and connecting intra-wall paths can bepreformed in the polymer, which microporous polymer is then manufacturedas wall 12 of system 10. In another, and presently preferred embodiment,wall 12 contains a multiplicity of pore-formers, not shown, that aredissolved or leached from wall 12, which is integrally manufactured assystem 10. In this embodiment, the pore-formers are removed when system10 is in the environment of use, thereby forming microporous wall 12 inthe environment.

The microporous paths of wall 12 are prefilled or filled in theenvironment of use with a diffusive medium permeable to the passage ofagent 17. The medium is generally non-toxic and it does not adverselyeffect the system, the wall, the agent and the environment. In oneembodiment, the medium is a liquid phase comprised of a solution, acolloidal medium, or a sol, the medium can be polar, semi-polar ornon-polar, or it can be a liquid present in the environment of use,including water, biological fluids, saline, and buffers.

Partition 14 of system 10 consists, in one embodiment, of a film made ofa semipermeable polymer that is essentially impermeable to the passageof agent, osmotic solute and polymer and is permeable to the passage offluid that enters system 10; and, in another embodiment partition 14 ismade of a film impermeable to agent, solutes, polymers and fluid.Partition 14 is suitably joined to wall 12 during manufacture of system10, and in a presently preferred embodiment it can contain a plasticizerthat imparts flexibility and expandibility to partition 14. Inoperation, when compartment 16 contains polymer 18, the polymer 18absorbs fluid that enters compartment 16 causing 18 to swell, expand andfill compartment 16, and also, swell and expand against partition 14,causing it to move and occupy the space of compartment 15. This actioncorrespondingly reduces the amount of space available for agent 17, andthis continual decrease in space substantially keeps agent 17 in asubstantially saturated phase.

In FIG. 2b, another system 10 is provided according to the mode and themanner of invention. System 10 of FIG. 2b is similar to system 10 ofFIG. 2a, with system 10 of FIG. 2b embracing other structuralembodiments. The embodiments of FIG. 2b include wall 12 having at leastone surface 12a formed of a semipermeable polymer. When wall 12a isformed of a semipermeable polymer, space 16 contains a member selectedfrom the group consisting essentially of an osmotically effective soluteand a swellable polymer 18. When space 16 houses the solute or theswellable polymer, partition 14 is formed of a member selected from thegroup consisting of a semipermeable polymer, and an impermeable polymer.When space 16 contains an osmotic solute, in operation it imbibes fluidthrough semipermeable wall 12a in a tendency towards osmoticequilibrium, to dissolve the solute and form a solution that fills space16, apply pressure against partition 14, urging it to move into space 15and decrease its volume, thereby keeping the beneficial agent present atthe microporous wall 12. When space 16 contains a swellable polymer, itabsorbs fluid, expands, but does not dissolve in fluid that enters space16. The expanding polymer pushes against partition 14 causing it to moveinto space 15, thereby keeping agent 17 in a saturated state at therelease rate wall.

FIG. 3 shows a system 10 designed, shaped, sized and styled for easyplacement and comfortable retention in a body passageway, such as thevagina, or the ano-rectal passageways. System 10 has a elongated,cylindrical, self-sustaining shape with a pointed lead end 19, atrailing end 20, and it is equipped with manually controlled cords 21for easily removing device 10 from a body passageway. Device 10 of FIG.3 is structurally identical with device 10 of FIGS. 1, 2a and 2b, and itoperates in a like manner, with element 16 expanding for continuallyoccupying area and void space in element 15 created by agent 17diffusing through micropores 13. Device 10 of FIG. 3 contains a drugdesigned for release and absorption by the vaginal or the rectal mucosa.

FIG. 4 compares the results obtainable with a system made without thespace consuming, saturation maintaining internal structure provided bythis invention, with the results obtainable with a system made with thespace consuming saturation maintaining internal structure provided bythis invention. The figure depicts for the former system a saturationstate S₁ having an early receding diffusional boundary layer, and forthe latter system saturated state S₂, which for this system representsan increased length of time the saturation state is present from S₁ toS₂. This increase in time t, is accompanied by a delay in the appearanceof the receding diffusional boundary layer, and a prolonged length oftime the agent is delivered at a zero order rate of release.

FIG. 5 illustrates an extruder that can be used for blending agentformulations housed in delivery system 10. In FIG. 5, extruder 22consists of a filling hopper 23, a screw 24 longitudinally extended inextruder 22, a drive journal 26 for turning screw 24 and an extruder die25 at the terminus of screw 24 for extruding blended formulations. Inuse, agent and blending ingredients, in powder or granule form, are fedinto hopper 23 for continuous feeding to screw 24, where they rollaround while the screw is turning, thereby homogenizing and blending theingredients. The ingredients are finally extruded through die 25 assystem intermediates that are eventually manufactured into system 10.

While FIGS. 1 through 3 are illustrative of various systems that can bemade according to this invention, it is to be understood those systemsare not to be construed as limiting the invention, as the systems cantake a wide variety of shapes, sizes and forms for delivering an agent,including drugs, to different enviroments of use. For example, thesystems include buccal, implant, eye, artificial gland, cervical,intrauterine, ear, nose, dermal, subcutaneous, and blood deliverysystems. The systems can be used in hospitals, veterinary clinics,nursing homes, sickrooms, and the like.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, it has now been foundthat diffusion delivery system 10 can be manufactured with microporouswall 12, formed from microporous polymers that are commerciallyavailable, or they can be made by art known methods. The microporousmaterials can be made, and then manufactured into a system, by etchednuclear tracking, by cooling a solution of a flowable polymer below itsfreezing point whereby solvent evaporates from the solution in the formof crystals dispersed in the polymer, and then curing the polymerfollowed by removing the solvent crystals, by cold or hot stretching ofa polymer at low or high temperatures until pores are formed, byleaching from a polymer a soluble pore forming component by use of anappropriate solvent, by ion exchange reactions consisting of exchanginga large space occupying ion with a smaller ion, by polyelectrolyticprocesses, and by dissolving or leaching a pore former from the wall ofa system in operation in the environment of use. Processes for preparingmicroporous materials are described in Synthetic Polymer Membranes, byR. E. Kesting, Chapters 4 and 5, 1971 published by McGraw Hill, Inc;Chemical Reviews, Ultrafiltration, Vol. 18, pages 373 to 455, 1934;Polymer Eng. and Sci., Vol. 11, No. 4, pages 284 to 288, 1971; J. Appl.Poly. Sci., Vol. 15, pages 811 to 829, 1971; and in U.S. Pat. Nos.3,565,259; 3,615,024; 3,751,536; 3,801,692; 3,852,224; and 3,849,528.

Materials useful for making the microporous wall 12 includepolycarbonates comprised of linear polyesters of carbonic acid in whichcarbonate groups recur in the polymer chain, microporous materialsprepared by the phosgenation of a dihydroxyl aromatic such as abisphenol A, microporous poly (vinylchloride), microporous polyamidessuch as polyhexamethylene adipamide, microporous modacrylic copolymersincluding those formed from poly(vinylchloride) 60% and acrylonitrite,microporous styrene-acrylic copolymers, porous polysulfonescharacterized by diphenylene sulfone groups in a linear chain thereof,halogenated poly(vinylidene), polychloroethers, acetal polymers,polyesters prepared by esterification of a dicarboxylic acid oranhydride with an alkylene polyol, poly(alkylenesulfides), phenolicpolyesters, microporous poly(saccharides), microporous poly(saccharides)having substituted anhydroglucose units exhibiting a decreasepermeability to the passage of water and biological fluids, asymmetricporous polymers, cross-linked microporous olefin polymers, hydrophobicor hydrophilic microporous homopolymers, copolymers having a reducedbulk density, and materials described in U.S. Pat. Nos. 3,595,752;3,643,178; 3,654,066; 3,709,774; 3,718,532; 3,803,061; 3,852,224;3,852,388; and 3,853,601, in British Pat. No. 1,126,849, and in Chem.Abst., Vol. 71 427F, 22573F, 1969.

The pore-formers useful for forming microporous wall 12 in theenvironment of use include solids and pore-forming liquids. In thelatter expression, the term for this invention generically embracessemi-solids and viscous fluids. The pore-formers can be inorganic ororganic and the wall forming polymer usually contains from 5 to 95% byweight. The term pore-former for both solids and liquids includesubstances that can be dissolved, extracted or leached from themicroporous precursor wall by fluid present in the environment of use toform operable, open-celled type microporous walls. Additionally, thepore-formers suitable for the invention include pore-formers that can bedissolved, leached, or extracted without causing physical or chemicalchanges in the polymer. The pore-forming solids have a size of about 100angstroms to 200 microns, and they include alkali metal salts such aslithium carbonate, sodium chloride, sodium bromide, sodium carbonate,potassium chloride, potassium sulfate, potassium phosphate, sodiumbenzoate, sodium acetate, sodium citrate, potassium nitrite, and thelike. The alkaline earth metal salts such as calcium phosphate, calciumnitrate, calcium chloride, and the like. The transition metal salts suchas ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,manganese fluoride, manganese fluorosilicate, and the like. Organiccompounds such as polysaccharides including pentoses, hexoses,disaccharides, sugars, sucrose, glucose, fructose, manitol, mannose,galactose, aldohexose, altrose, talose, sorbitol, and the like,carboxy-polymethylene, Carbowax® compounds, polysorbate, and the like.The pore-formers are non-toxic and on their removal from the wall,channels or paths are formed through wall 12, that fill with fluid. Thepaths become a means, or diffusional path for diffusion of agent, ordrug from the system. The pores extend from inside wall 12 to the outiseof wall 12 for effective release of agent or drug to the exterior ofsystem 10.

Additional micropores materials for forming wall 12 include microporouspoly(urethanes), cross-linked, chain-extended microporouspoly(urethanes), microporous poly(urethanes) in U.S. Pat. No. 3,524,753,micorporous poly(imides), microporous poly(benzimidazoles), regeneratedmicroporous proteins, semi-solid cross-linked microporouspoly(vinylpyrrolidone), microporous materials prepared by diffusion ofmultivalent cations into polyelectrolyte sols as in U.S. Pat. No.3,565,259, anisotropic permeable microporous materials of ionicallyassociated polyelectrolytes, microporous polymers formed by thecoprecipitation of a polycation and a polyanion as described in U.S.Pat. Nos. 3,276,589; 3,541,006; 3,541,055; and 3,546,142, microporousderivatives of poly(styrene) such as microporous poly(sodiumstyrene-sulfonate) and microporous poly(vinyl benzyltrimethyl-ammoniumchloride), the microporous materials disclosed in U.S. Pat. No.3,615,024 and U.S. Pat. Nos. 3,646,178 and 3,852,224.

The selective permeable polymers used for partition 14 and wall 12a,when a semipermeable polymer is used for their manufacture in system 10,include, polymers permeable to fluid present in system 10 and theenvironment, while remaining impermeable to solutes, agents and drugs.Typical materials include semipermeable polymers, also known to the artas osmosis membranes. The semipermeable polymers include celluloseacrylate, cellulose diacylate, cellulose triacylate, cellulose ethersand cellulose esters. Typical semipermeable polymers include celluloseacetate, cellulose acetate ethyl carbamate, and the like. Othersemipermeable polymers include polyurethane, and selectively permeablepolymers formed by the coprecipitation of a polyanion and a polycation,and semipermeable ion exchange polymers. Generally, semipermeablepolymers useful for forming partition 14, or wall 12a, will have a fluidpermeability of 10⁻⁵ to 10⁻¹ (cc mil/cm² hr atm) expressed peratmosphere of hydrostatic or osmotic pressure difference across 14 or12a at the temperature of use.

Exemplary polymers suitable for partition 14, when it is impermeable tofluid agents and solutes include, plasticized polyvinyl chloride,styrene-butadiene block copolymer, polyester-polyethers,ethylene-propylene copolymer, segmented block polyurethane, chlorinatedpolyethylene, ethylene vinylchloride copolymer, and the like. Thepartition in both designs, can contain a plasticizer to increase itsflexibility during use.

Exemplary plasticizers suitable for adding to partition 14 to impartflexibility and stretchability include cyclic and acyclic plasticizers.Typical plasticizers are those selected from the group consisting ofphthalates, phosphates, citrates, adipates, tartrates, sebacates,succinates, glycolates, glycerolates, benzoates, myristates,sulfonamides, halogenated phenyls, glycols, diols, and polyols.

Exemplary plasticizers further include dialkyl phthalates, dicycloalkylphthalates, diaryl phthalates and mixed alkyl-aryl phthaltes asrepresented by dimethyl phthalate, dipropyl phthalate,di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate anddicapryl phthalate; alkyl and aryl phosphates such as tributylphosphate, trioctyl phosphate, tricresyl phosphate, trioctyl phosphate,tricresyl phosphate and triphenyl phosphate; tricresyl phosphate,trioctyl phosphate, tricresyl phosphate and triphenyl phosphate; alkyland aryl phosphates such as tributyl phosphate, trioctyl phosphate,tricresyl phosphate, trioctyl phosphate, tricresyl phosphate andtriphenyl phosphate; alkyl citrate and citrates esters such as tributylcitrate, triethyl citrate, and acetyl triethyl citrate; alkyl adipatessuch as dioctyl adipate, diethyl adipate and di(2-methoxyethyl)-adipate;dialkyl tartrates such as diethyl tartrates and dibutyl tartrate; alkylsebacates such as diethyl sebacate, dipropyl sebacate and dinonylsebacate; alkyl succinates such as diethyl succinate and dibutylsuccinate; alkyl glycolates, alkyl glycerolates, glycol esters andglycerol esters such as glycerol diacetate, glycerol triacetate,glycerol monolactate diacetate, methyl phythayl ethyl glycolate, butylphthalyl butyl glycolate, ethylene glycol diacetate, triethylene glycoldibutyrate and triethylene glycol dipropionate. Other plasticizersinclude camphor, N-ethyl-(o- and p-toluene) sulfonamide, chlorinatedbiphenyl, benzophenone, N-cyclohexyl-ptoluene sulfonamide, substitutedepoxides, poly(alkylene glycols), poly(alkylene diols), esters ofalkylene glycols, and the like.

Suitable plasticizers can be selected for blending with partition 14forming materials by selecting plasticizers that have a high degree ofsolvent power for the materials, are compatible with the materials overboth the processing and use temperature ranges, exhibit permanence asseen by a strong tendency to remain in the plasticized partition andimparts flexibility to the partition. Procedures for selecting aplasticizer having the described characteristics are disclosed in theEncyclopedia of Polymer Science and Technology, Vol. 10, pages 228 to306, 1979, published by John Wiley & Sons, Inc., New York. Also, adetailed description pertaining to the measurement of plasticizerproperties, including solvent parameters and compatibility, theHildebrand solubility parameter, the Flory-Huggins interactionparameter, and the cohesive-energy density, CED, parameter is disclosedin Plasticization and Plasticizer Processes, Advances in ChemistrySeries 48, Chapter 1, pages 1 to 26, 1965, published by the AmericanChemical Society, Washington, D.C. The amount of plasticizer addedgenerally is an amount sufficient to produce the desired film and itwill vary according to the plasticizer and the materials. Usually about0.001 part up to 25 parts, or higher, of the plasticizer can be used for100 parts partition forming material with a presently preferred range of0.1 part to 15 parts of plasticizer, or mixtures thereof for 100 partsof partition forming materials.

The swellable polymer that can be used as driving member 18 forexpanding and enlarging space 16, and for pushing partition 14, as inFIGS. 2a and 2b, into agent space 15, or for swelling and expandingwhile correspondingly decreasing the agent containing space, aregenerally lightly cross-linked hydrophilic polymers. These polymers, onswelling, reduce the amount of space available for agent 17, and thiscontinual decrease in space acts to substantially maintain agent 17 in asubstantially saturated phase. The formulation and maintenance at theagent microporous wall boundary layer in system 10, at substantially thesame rate and amount throughout the release period, produces for system10, a prolonged zero order rate.

Representative polymers are those that swell in the presence of fluid toa high degree without dissolution, are lightly cross-linked, usuallyexhibiting a 5 to 50 fold volume increase. Exemplary polymers arecross-linked hydrogels including poly(hydroxyalkylmethacrylates),poly(acrylamide), poly(methacrylamide), poly(N-vinyl-2-pyrrolidone),anionic and cationic hydrogels, polyelectrolyte complexes, awater-insoluble, water-swellable copolymer produced by forming adispersion of finely divided copolymers of maleic anhydride withstyrene, ethylene, propylene, butylene or isobutylene cross-linked withfrom about 0.001 to about 0.5 moles of a polyunsaturated cross-linkingagent per mole of maleic anhydride in the copolymer as disclosed in U.S.Pat. No. 3,989,586, the water-swellable polymers of N-vinyl lactams asdisclosed in U.S. Pat. No. 3,992,562, semi-solid cross-linked poly(vinylpyrrolidone), diester cross-linked polyglucan hydrogels as described inU.S. Pat. No. 4,002,173, the anionic hydrogels of heterocyclic N-vinylmonomers as disclosed in U.S. Pat. No. 4,036,788, the ionogenichydrophillic gels as described in J. Biomedical Mater. Res., Vol. 7,pages 123 to 126, 1973, and the like.

The osmotically effective compound that can be used in space 16, whenpartition 14 is formed of a polymer selected from the group consistingof a semipermeable and impermeable polymer, and when wall 12a is made ofa semipermeable polymer include organic and inorganic compounds orsolutes that exhibit an osmotic pressure gradient across semipermeablewall 12a against fluid in the environment, or across a semipermeablepartition 14 against fluid in agent space 15. Osmotically effectivecompounds useful for this purpose include magnesium sulfate, magnesiumchloride, sodium chloride, lithium chloride, potassium sulfate, sodiumcarbonate, potassium acid phosphate, mannitol, urea, sucrose, and thelike. The osmotically effective compounds are also known as osmagentsand they are disclosed in U.S. Pat. Nos. 3,854,770 and 4,077,407. Thesepatents are assigned to the Alza Corporation of Palo Alto, Calif.

The expressions "active agent" and "beneficial agent" as used hereinbroadly include any compound, composition of matter, or mixture thereof,that can be delivered from system 10 to produce a beneficial and usefulresult. The active agents include air purifiers, algicides,antioxidants, biocides, catalysts, chemical reactants, cosmetics,contraceptives, drugs, disinfectants, food supplements, fermentationagents, fertility inhibitors, fertility promoters, fungicides,germicides, herbicides, insecticides, micro-organism attenuators,pheremones, pro-drugs, plant growth inhibitors, pesticides,preservatives, rodenticides, sex sterilants, slimicides, vitamins andother agents that benefit the environment of use and mankind.

Representative of drugs that can be delivered by system 10 includetransquilizers such as reserpine, thropropazate, perphenazine andchloropromazine; psychic energizers such as amitriplyline, imipramineand methylphenidate; analgesics-antipyretics such as aspirin, phenacetinand salicylamide indomethacin, and diclofenac; anti-inflammatories suchas hydrocortisone, dexamethazone, prednisolone, and phenylbutazone;decongestants such as phenylephrine and pseudoephedrine; antibioticssuch as erythromycin, tetracycline, minocyline, etc., cardiovasculardrugs such as quinidine; and other agents.

Representative of drugs that can be dispensed in the vagina from asystem sized, shaped and adapted for easy insertion and comfortableretention in the vagina include allantorn, aminoacridine hydrochloride,benzocaine, benzalkonium chloride, candicidin, dienestrol., dibucaine,ephedrine sulfate, furazoldione, gentain violet, hydrocortisone,methylbenzethium chloride, phenylmercuric acetate, providone-iodine,sulfanilamide, sulfisoxazole, tetracaine, undecylenate, and the like.See Techniques of Medication, by Eric W. Martin, pages 106 to 107, 1969,published by J. B. Lippincott Company, Philadelphia.

Representative of drugs that can be dispensed in the ano-rectalenvironment from a system shaped, sized and adapted for easy insertionand comfortable retention therein include acetarsol, adrenaline withbenzocaine, aminophylline, aminophylline with phenobarbitol sodium,ampicillin, aspirin, astroscopolamine, belladonna, benzocaine,bisacodyl, bismuth subgallate, cafferine, ergotamine tartrate,chloralhydrate, chlorpromazine, cinchocaine, cyclomethycaine sulfate,dimenhydrinate, hydrocottisone, ichthammol, isoprenaline, metronidazole,morphine, oxymorphine hydrodiamine, thiethylperzaine meleate, and thelike. See Martindale The Extra Pharmacopolia, Edited by Ainley Wade,General Index, page 2056, 1977, published by the Pharmaceutical Press,London; and, National Drug Code Directory, 1972, published by PublicHealth Service, U.S. Department of Health, Education and Welfare,Washington, D.C.

The drug present in system 10 can be in various forms, such as unchargedmolecules, molecular complexes, pro-drug, pharmacological acceptablesalts such as hydrochlorides, hydrobromides, sulfate, laurylate,palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate,oleates, and salicylate. For acidic drugs, salts of metals, amines, ororganic cations, for example, quaternary ammonium salts can be used.Derivatives of drugs such as esters, ethers and amides, which havesolubility characteristics suitable for use herein can be used. Theagent or drug can be in the compartment as a suspension, dispersion,paste, cream, particle, granule, emulsion, solution, powder, and thelike.

The amount of agent in system 10 is preferably initially in excess ofthe amount that can be dissolved in fluid that enters the agent housingspace. Under this physical state, when agent 17 is in excess, system 10will diffusingly operate to give a substantially constant rate ofrelease over time, then member 18 activates and the combined action ofmember 18 and system 10 operating as a unit system producing asubstantially constant rate of release over a prolonged period of time.The length of time agent is released can also be varied by havingdifferent amounts of agent in system 10 to form saturated solutionscontaining saturated concentrations of agent for delivery from thesystem 10. Generaly, system 10 can house from 0.01 ng to 7 g or more,with individual devices containing for example 25 ng, 1 mg 100 mg, 250mg, 500 mg, 1.5 g., 5 g, 7.5 g, 7.5 g, 10 g, and the like.

The systems of the invention are manufactured by standard techniques.For example, in one embodiment a swellable polymer or a compressedamount of an osmotic solute are independently coated on one surface witha partition forming polymer, and then a compressed amount of agent,having a shape that corresponds to the shape of the polymer or solute.Next, a microporus wall forming the system can be applied by molding,spraying or dipping the system intermediate into a wall forming materialto completely surround the intemediate and yield the system. In anotherembodiment, a microporous wall can be partly cast in a preshaped mold tothe desired dimension defining the wall that surrounds an internalspace, the space partly filled with a mass of agent, followed by a layerof a partition and then a mass of a driving force. The remainder of thewall abutting the driving force, is formed from a microporus orsemipermeable polymer for closing the device. Walls forming the systemalso can be joined by various joining techniques, such as high frequencyelectronic sealing that provides clean edges and firmly formed walls.Another, and presently preferred technique that can be used is the airsuspension procedure. Air suspension preocedures are described in U.S.Pat. No. 2,799,241; in J. AM. PHARM. ASSOC., Vol 49, pages 82 to 84,1960. Other wall forming techniques include pan coating, in which thematerials are deposited by successive tumbling and spraying of thepolymer solution on the agent and the driving member tumbling in arotating pan. Other standard manufacturing procedures are described inModern Plastic Enclyclopedia, Vol. 46, pages 62 to 70, 1069; and inPharmaceutical Sciences, by Remington, 14th Ed., pages 1626 to 1678,1970, published by Mack Publishing Company, Easton, Pa.

Exemplary solvents suitable for manufacturing the wall, or the partitioninclude inert inorganic and organic solvents that do not adversely harmthe wall forming materials, the partition forming materials, and thefinal device. The solvents broadly include members selected from thegroup consisting of aqueous solvents, and organic solvents, such asalcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenatedsolvents, cycloapliphatics, aromatics, heterocyclic solvents andmixtures thereof. Typical solvents include acetone, diacetone, alcohol,methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate,ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, methyl ether, ethylene glycol monoethyl acetate, methylenedichloride, ethylene dichloride, propylene dichloride, carbontetrachloride, nitroethane, itropropane, tetrachloroethane, ethyl ether,isopropyl either, cyclohexane clyclo-octane, benzene, toluene, naphtha,1, 4-dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof suchas acetone and water, acetone and methanol, acetone and ethyl alcohol,methylene dichloride and methanol, and ethylene dichloride andemethanol.

The following examples are merely illustrative of the present inventionthat produces devices that keep their physical and chemical integrityduring their delivery history, and they should not be considered aslimiting the scope of the invention in any way, as this example andother equivalents thereof will become more apparent to those versed inthe art in the light of the present disclosure, the drawings, and theaccompanying claims.

EXAMPLE 1

First, 125 mg of the osmotic solute sodium chloride is compressed to apreselected shape and coated on one of its surface with a partitionforming compostion comprising 70% cellulose acetate having an acetylcontent of 32% mixed with 30% polyethylene glycol having a molecularweight of 400 dissolved in methylene chloride methanol, 80:20, wt:wt,until an expandable partition is formed on the solute.

Next, 235 mg of dry antiarrhythmic and antifirbrillatoryp-amino-N(2-diethylamineothyl)-benzamide hydrochloride having amolecular weight of 271.19 is compressed into a shape that correspondsto the shape of the solute, and placed onto the available surface of thepartition. Next the device intermediate comprising of the solute,partition and drug is surrounded with a microporous wall. Themicroporous wall is formed form a compostion consisting of 65 g ofcellulose acetate having an acetyl content of 32%, 41 g of thepore-former sorlitol, 11.7 g of polyethylene glycol 400, and a wallforming solvent consisting 1900 ml of acetone and 375 ml of water. Thewall is formed by air tumbling until a 7 mil thick microporous wall isformed on the system to produce a system manufactured as an oral device.

EXAMPLE 2

A therapeutic system is manufactured in the form of an oral device fordelivering procainamide hydrochloride to the gastrointestinal tract or awarm-blooded animal as follows: first, 200 mg of lightly cross-linked,water swellable, water insoluble polyvinyl alcohol is coated on onesurface with a layer of partition forming composition consisting of 70%cellulose acetate having an acetyl content of 32% mixed with 30%polyethylene glycol having a molecular weight of 400 and dissolved inmethylene chloride: methanol, 80:20, wt:wt, until a semipermeablepartition is formed. Next, 235 mg of procainamide hydrochloride having amolecular weight of 271.79 is pressed onto the partition in the form ofa solid mass having a shape corresponding to the shape of the polyvinylalcohol. Then the just-formed drug-polymer composite device intermediateis surrounded on all surfaces, except the surface of the polymer distantfrom the partition, with a wall of microporous polymeric polypropylenehaving a void volume of 0.565 to 0.075 cm³ /gm, a density of 0.60 to0.85 gm/cm³, and a pore size of 150 to 5000 angstroms, as disclosed inU.S. Pat. No. 3,426,754. Finally, the exposed surface of the polyvinylalcohol polymer is coated with a wall of cellulose acetate having anacetyl content of 38.3% to yield the device.

EXAMPLE 3

The device of example 1, is manufactured in this example, except that inthis example, the partition is formed of highly plasticizedpoly(monochloroethylene).

EXAMPLE 4

The procedures of example 1 and 2 are repeated with all conditions aspreviously described, except the agent in the agent space is selectedfrom the group consisting of hypnotics, sedatives, psychic energizers,tranquilizers, anticonvulsants, muscle relaxants, antiparkinson,analgesics, anti-inflammatory, anesthetic, muscle contractants,anti-microbiols, antimalarials, hormones, sympathomimetic, duiretics,hypoglcmics and nutritional agents.

EXAMPLE 5

A device for orally administering a useful drug is made as follows:first, 500 mg of dry, quinidine is pressed in a Manesty tabletingmachine to a Stoke's hardness of about 8 kg. Then, 350 mg of lightlycross-linked poly(hydroxyalkyl methacrylate), having a shapecorresponding to the shape of the drug, is pressed firmly onto onesurface of the drug, to yield the device intermediate. Next, amicroporous wall of poly(vinyl chloride) with continous diffusionalpaths is prepared by leaching a sheet of polymer consisting on thepoly(vinyl chloride) containing the pore forming agentpoly(p-dimethylamino styrene). The wall is formed by casting in asolvent of cyclohexane and the solvent evaporated. Then, an aqueousacidic solution of hydrochloric acid is used to leach the pore formersand yield the microporous wall. The leaching is carried out at roomtemperature followed by washing with distilled water to remove the acid.The device intermediate is surrounded with the wall to yield the device.

The novel systems of this invention uses an expandable member for theobtainment of precise diffusional release rates and enhanced delivery ofagent to environments of use while simultaneously maintaining theintegrity and character of the systems. And, while there has beendescribed and pointed out features of the invention as applied topresently preferred embodiments, those skilled in the art willappreciate that various modifications, changes, additions and omissionsin the device illustrated and described that can be made withoutdeparting from the spirit of the invention.

I claim:
 1. A diffusor for the controlled delivery of a beneficial agentat a zero order rate of release for an increased length of time to afluid environment of use, the diffusor comprising:a. a wall formed inpart of a microporous polymer with the remaining part formed of asemipermeable polymer surrounding and forming; b. a compartment havingan internal space; c. a beneficial agent in the compartment occupyingpart of the space; d. an osmotically effective solute in the compartmentoccupying the remainder of the space, said solute in contact with thepart of the wall formed of a semipermeable polymer; and, e. a flexiblepartition formed of a member selected from the group consisting of asemipermeable polymer and an impermeable polymer in the compartment,which partition is joined to the wall and placed between the beneficialagent and the osmotic solute.
 2. The diffusor for the controlleddelivery of beneficial agent according to claim 1, wherein, when thediffusor is in the fluid environment fluid is imbided through thesemipermeable wall into the space occupied by the solute, causing it todissolve and form a solution that fills the space and moves thepartition, with the partition compressing the beneficial agent againstthe microporous wall, thereby keeping it in a saturated state for anincreased length of time and concomitantly increasing the length of timethe beneficial agent is released from the diffusor at a zero order rateof release.
 3. The system for the controlled delivery of the beneficialagent according to claim 1, wherein the wall of the system distant fromthe partition and in contact with the member in the second space has asection or is totally formed of a semipermeable polymer.
 4. The systemfor the controlled delivery of the beneficial agent according to claim1, wherein the wall of the system distant from the partition and incontact with the member in the second space has a section formed of asemipermeable polymer, the partition is formed of a semipermeablepolymer and the second space houses an osmotically effective solute. 5.A process for delaying the appearance of a receding diffusional boundarylayer according to claim 1, wherein the microporous wall has a sectionreplaced with a semipermeable wall, which semipermeable wall is incontact with the second space.
 6. The diffusor for the controlled andcontinuous delivery of agent according to claim 1, wherein theenvironment of use is a human, the fluid is a biological fluid, theagent is a drug, and the diffusor is sized, shaped and structured forplacement and retention in said environment.
 7. The diffusor for thecontrolled and continuous delivery of agent according to claim 1,wherein the micropaths in the wall are formed in the environment of useby fluid leaching a pore-former from the wall.
 8. The diffusor for thecontrolled and continuous delivery of a beneficial agent according toclaim 1, wherein the agent is a member selected from the groupconsisting of tranquilizers, psychic energizers, analgesics,antipyretics, anti-inflammatories, hormones, oral drugs, vaginal drugsand ano-rectal drugs.